Immunoproteasomes shape immunodominance hierarchies of antiviral CD8(+) T cells at the levels of T cell repertoire and presentation of viral antigens

Vertebrates express three cytokine-inducible proteasome subunits that are i ncorporated in the place of their constitutively synthesized counterparts. There is increasing evidence that the set of peptides generated by proteaso mes containing these subunits (immunoproteasomes) differs from that produce d by standard proteasomes. In this study, we use mice lacking one of the im munoproteasome subunits (LMP2) to show that immunoproteasomes play an impor tant role in establishing the immunodominance hierarchy of CD8(+) T cells ( TCD8+) responding to seven defined determinants in influenza virus. In LMP2 (-/-) mice, responses to the two most dominant determinants drop precipitou sly, whereas responses to two subdominant determinants are greatly enhanced . Adoptive transfer experiments with naive normal and transgenic TCD8+ reve al that the reduced immunogenicity of one determinant (PA(224-233)) can be attributed to decreased generation by antigen presenting cells (APCs), wher eas the other determinant (NP366-374) is less immunogenic due to alteration s in the TCD8+ repertoire, and not, as reported previously, to the decrease d capacity of LMP2(-/-) APCs to generate the determinant. The enhanced resp onse to one of the subdominant determinants (PB1F2(62-70)) correlates with increased generation by LMP2(-/-) virus-infected cells. These findings indi cate that in addition to their effects on the presentation of foreign antig ens, immunoproteasomes influence TCD8+ responses by modifying the repertoir e of responding TCD8+.